Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; Manchester Heart Centre, Central Manchester University Hospitals NHS Trust, Manchester, United Kingdom.
Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom.
Heart Rhythm. 2018 May;15(5):752-760. doi: 10.1016/j.hrthm.2017.12.027. Epub 2017 Dec 27.
Aging is associated with an increased incidence of atrioventricular nodal (AVN) dysfunction.
The aim of this study was to investigate the structural and functional remodeling in the atrioventricular junction (AVJ) with aging.
Electrophysiology, histology, and immunohistochemistry experiments on male Wistar Hannover rats aged 3 months (n = 24) and 2 years (n = 15) were performed. Atrio-His (AH) interval, Wenkebach cycle length (WBCL), and AVN effective refractory period (AVNERP) were measured. Cesium (2 mM) was used to block hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, while ryanodine (2 μM) was used to block ryanodine 2 (RyR2) channels. Protein expression from different regions of the AVJ was studied using immunofluorescence. The expression of connexins (connexin 43 and connexin 40), ion channels (Hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4), voltage sensitive sodium channel (Na1.5), and L-Type calcium channel (Ca1.3)), and calcium handling proteins (RyR2 and sarco/endoplasmic reticulum calcium ATPaset type 2a (SERCA2a)) were measured. Morphological characteristics were studied with histology.
Without drugs to block HCN and RyR2 channels, there was prolongation of the AH interval, WBCL, and AVNERP (P < .05) with aging. In young rats only, cesium prolonged the AH interval, WBCL, and AVNERP (P < .01). Ryanodine prolonged the AH interval and WBCL (P < .01) in both young and old rats. Immunofluorescence revealed that with aging, connexin 43, HCN4, Na1.5, and RyR2 downregulate in the regions of the AVJ and connexin 40, SERCA2a, and Ca1.3 upregulate (P < .05). Aging results in cellular hypertrophy, loosely packed cells, a decrease in the number of nuclei, and an increase in collagen content.
Heterogeneous ion channel expression changes were observed in the AVJ with aging. For the first time, we have shown that HCN and RyR2 play an important role in AVN dysfunction with aging.
随着年龄的增长，房室结（AVN）功能障碍的发生率增加。
本研究旨在探讨与年龄相关的房室结（AVJ）的结构和功能重塑。
对 3 月龄（n=24）和 2 岁（n=15）雄性 Wistar 汉诺威大鼠进行电生理学、组织学和免疫组织化学实验。测量房室结（AVN）有效不应期（AVNERP）、文氏周期（Wenkebach cycle length，WBCL）和房室结（atrioventricular node，AVN）的文氏周期（Wenkebach cycle length，WBCL）和房室结（atrioventricular node，AVN）的有效不应期（AVNERP）。使用 2 毫摩尔的铯（cesium，2 mM）阻断超极化激活环核苷酸门控（hyperpolarization-activated cyclic nucleotide-gated，HCN）通道，而使用 2 微摩尔的钇（ryanodine，2 μM）阻断 Ryanodine 2（Ryanodine 2，RyR2）通道。使用免疫荧光法研究 AVJ 不同区域的蛋白表达。测量连接蛋白（连接蛋白 43 和连接蛋白 40）、离子通道（HCN4、电压敏感钠通道（Na1.5）和 L 型钙通道（Ca1.3））和钙处理蛋白（RyR2 和肌浆/内质网钙 ATPase 型 2a（SERCA2a））的表达。使用组织学研究形态学特征。
在未用药物阻断 HCN 和 RyR2 通道的情况下，随着年龄的增长，AH 间期、WBCL 和 AVNERP 延长（P<.05）。仅在年轻大鼠中，铯延长了 AH 间期、WBCL 和 AVNERP（P<.01）。钇延长了年轻和老年大鼠的 AH 间期和 WBCL（P<.01）。免疫荧光显示，随着年龄的增长，AVJ 区域的连接蛋白 43、HCN4、Na1.5 和 RyR2 下调，而连接蛋白 40、SERCA2a 和 Ca1.3 上调（P<.05）。衰老导致细胞肥大、细胞排列松散、细胞核数量减少和胶原含量增加。
随着年龄的增长，房室结（AVN）出现异质性离子通道表达变化。我们首次表明，HCN 和 RyR2 在衰老过程中房室结（AVN）功能障碍中起重要作用。
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